To improve therapeutic strategies, we propose to dissect primary (intrinsic) resistance of a given melanoma to a panel of inhibitors with distinct modes of action. Our preliminary studies demonstrate that following a given drug treatment, melanoma cells not only enter apoptosis and necrosis, but they can also respond via one of two senescent phenotypes. These include either a natural irreversible (terminal) senescence, or a second type of senescence that we have recently observed, which, while bearing the hallmarks of classical senescence, is reversible. Due to the fact that this reversible senescence can have tumor-protective properties and give rise to a proliferative population, we term it pseudo senescence. This proposal is designed to define the role of therapy-induced senescence in melanoma and to develop novel therapeutic strategies that promote irreversible senescence and sensitize cells to therapy-induced apoptosis. In the first aim we will define therapy-induced senescence and will determine the molecular mechanisms underlying the heterogeneous responses to signaling modulators/inhibitors, including novel BRAF dimer inhibitors. It is likely that each type of senescence will have different outcomes, ranging from eventual cell death to the increase of invasion followed by re-growth. Our studies will assess the different cell fates to best define the mechanisms leading to the terminal senescence, and ultimately, cell death in combination with other reagents. In the second aim, we will develop therapeutic strategies for maximizing the induction of senescence/cell death in melanomas. We will test the hypothesis that pro-survival autophagy modulates the long-term responses to senescence induction and will develop combination therapies to induce irreversible senescence.